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Assessment of tumor response in malignant pleural mesothelioma
Cancer Treatment Reviews (2007) 33, 533– 541
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctrv
CONTROVERSY
Assessment of tumor response in malignant pleural mesothelioma Giovanni L. Ceresoli a,*, Arturo Chiti b, Paolo A. Zucali a, Federico Cappuzzo a, Fabio De Vincenzo a, Raffaele Cavina a, Marcello Rodari b, Dario Poretti c, Fabio Romano Lutman c, Armando Santoro a a b c
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy Department of Nuclear Medicine, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy Department of Radiology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
Received 13 June 2007; received in revised form 17 July 2007; accepted 25 July 2007
KEYWORDS Mesothelioma; Response evaluation; CT scan; PET; Serum markers
Summary Most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of their disease. Assessment of the response with conventional criteria based on computed tomography (CT) measurements is challenging, due to the circumferential and axial pattern of growth of MPM. Such difficulties hinder an accurate evaluation of clinical study results and make the clinical management of patients critical. Several radiological response systems have been proposed, but neither WHO criteria nor the more recent RECIST unidimensional criteria nor hybrid uni- and bidimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria for MPM have been published. Although they are already being used in current clinical trials, they have been criticized based on the high grade of inter-observer variability and on theoretical studies of mesothelioma growth according to non-spherical models. Computer-assisted techniques for CT measurement are being developed. The use of FDG-PET for prediction of response and, more importantly, of survival outcomes of MPM patients is promising and warrants validation in large prospective series. New serum markers such as osteopontin and mesothelin-related proteins are under evaluation and in the future might play a role in assessing the response of MPM to treatment. c 2007 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +39 02 82244080; fax: +39 02 82244590. E-mail addresses: [email protected] (G.L. Ceresoli), [email protected] (A. Chiti), [email protected] (P.A. Zucali), [email protected] (F. Cappuzzo), [email protected] (F. De Vincenzo), raffaele.cavina@ humanitas.it (R. Cavina), [email protected] (M. Rodari), [email protected] (D. Poretti), [email protected] (F.R. Lutman), [email protected] (A. Santoro).
0305-7372/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2007.07.012
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Introduction Malignant pleural mesothelioma (MPM) is an aggressive tumor which usually has a poor prognosis. Its incidence is increasing throughout most of the world, and it is predicted that it will rise in the next 10–15 years as a result of widespread exposure to asbestos in past decades.1 The management of patients with MPM remains controversial. Due to the usually advanced stage at presentation, only a minority of patients are eligible for radical surgery2; most are candidates for chemotherapy during the course of their disease. The relatively low incidence of the disease has made it difficult to conduct randomized controlled studies with adequate numbers of cases. Therefore, a nihilistic attitude has existed for many years regarding treatment of MPM, with retrospective studies reporting median survival of less than one year and 5-year survival rates of 1% or less.3 Several new cytotoxic agents with definite activity in mesothelioma have been evaluated in the last decade, including gemcitabine, vinorelbine and the antifolates pemetrexed and raltitrexed.4 Recently, two randomized controlled trials wherein single-agent cisplatin was compared with its combination with an antifolate have established the combination treatment as the reference regimen for first-line chemotherapy.5,6 More specifically, a large phase III trial testing pemetrexed and cisplatin versus cisplatin alone in 448 chemotherapy-naive patients with MPM showed a significant advantage with the combined regimen in survival, time to progression and response rate.5 Several biological agents have been explored or are currently under evaluation.7,8 Contrast-enhanced computed tomography (CT) is the primary imaging modality for the evaluation of MPM; rind-like extension of the tumor on the pleural surfaces is the most common CT feature, and is seen in up to 70% of cases.9–11 However, it lacks the ability to depict the extent of disease accurately. For patients being assessed for surgery, magnetic resonance imaging (MRI) can provide additional information in detecting chest wall and diaphragmatic invasion.12,13 On the other hand, the sensitivity and specificity of CT for mediastinal nodal involvement are very low, due to the unpredictable and not well characterized lymphatic pattern of spread of MPM.14 The use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of MPM has been described recently. FDG-PET has proved useful in detecting malignant pleural lesions15 and partially in assessing the extent of tumor involvement. In one study of 65 MPM patients, this imaging technique correctly detected extrathoracic metastases but failed to reliably identify the locoregional (tumor and mediastinal nodal) status of MPM16; sensitivity was 19% for locally advanced disease (T4) and 11% for nodal metastases. Integrated CTPET with coregistration of anatomic and functional imaging data increases the accuracy of MPM staging for T4 disease (sensitivity 67%, specificity 93%), while it remains inaccurate in the evaluation of nodal metastases (sensitivity 38%, specificity 78%), with high rates of false-positive and false-negative results.17,18 Further studies have demonstrated that FDG uptake, measured at diagnosis by standardized uptake value (SUV), has independent prognostic value in this disease. In a retrospective study of 137 patients with MPM, a SUV > 10 was significantly related to poor prognosis in multivariate analysis; patients with high SUV had a
G.L. Ceresoli et al. death hazard ratio of 1.9 compared to patients with SUV <10.19
CT-Based assessment of response: WHO, RECIST, new proposals Assessment of response with conventional criteria based on CT measurements is challenging in MPM, due to its circumferential and axial pattern of growth. Multiple thoracic levels may be involved; while there are anatomical landmarks in the upper and mid thorax, in the lower thorax there are few landmarks where levels of measurement can be reproducibly identified.20 Such difficulties hinder an accurate evaluation of clinical study results, particularly in phase II trials,21 and make the clinical management of patients critical. However, the recent development of more active regimens underlines the need for accurate techniques for evaluating response in this disease. Several response criteria have been proposed.20 In 1981, the World Health Organization (WHO) established the first quantitative criteria for measurement of solid tumors on imaging studies before and after chemotherapy.22 According to these response criteria, based on measurement of bidimensional lesions, a partial response (PR) was defined by a P50% decrease in the sum of the products of the longest diameter of each lesion and its perpendicular diameter; an increase of P25% of this sum was defined as progressive disease (PD). These criteria were poorly suited to the growth pattern of MPM. In early chemotherapy trials the need for ‘‘ad hoc’’ methods of evaluation was reported, and the introduction of unidimensional measurements was proposed.23 The RECIST criteria (Response Evaluation Criteria in Solid Tumors), which are widely used in clinical trials involving other solid tumors, use only unidimensional measurements of the longest diameter of the lesions.24 According to RECIST criteria, PR is defined by a P30% decrease in the sum of unidimensional measurements of target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, can be measured. PD is defined by a P20% increase of this sum. This approach is based on mathematical calculations of the volume changes of roughly spherical tumors, and therefore is poorly applicable to non-spherical tumors such as MPM. In MPM it is nearly impossible to establish which lesions should be considered as ‘‘target’’ or ‘‘nontarget’’, or to measure the longest diameter of the tumor. Van Klaveren et al.,25 in a series of 34 patients treated with chemotherapy, found very poor agreement between response evaluations according to WHO and RECIST criteria, with RECIST underscoring the tumor response and the tumor progression in most of cases; the percentage of patients in whom one or more discrepancies were detected was 47%. Similar results were reported by Monetti et al.26 in a more limited series of MPM patients. Hybrid uni- and bidimensional criteria have been proposed by other authors27 and used in other large trials, in particular in the landmark phase III trial of the combination of pemetrexed/cisplatin versus cisplatin alone.5 However, considerable discrepancy was reported among study investigators and independent reviewers in the evaluation of patients treated in this trial where tumor response could be confirmed in only half of
Assessment of tumor response in malignant pleural mesothelioma patients.28 Recently, modified RECIST criteria have been developed and validated by Byrne and Nowak.29 A total of 73 patients from two clinical trials of cisplatin/gemcitabine in MPM were reviewed. Tumor thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on transverse CT slices (Fig. 1); levels were at least 1 cm apart and related to anatomical landmarks to allow reproducible assessment at later time points. Bidimensionally measurable lesions, such as mediastinal lymph nodes, were recorded unidimensionally as for RECIST. The sum of the six measurements defined a pleural unidimensional measure. Criteria for PR and PD were the same as in the original RECIST system (Table 1). The response according to these modified RECIST criteria predicted longer patient survival (15.1 versus 8.9 months, P = 0.03) and improved respiratory function, with an increase of forced vital capacity during treatment (P < 0.0001). Although modified RECIST criteria are being used in most current clinical trials, they have been criticized based on the high grade of inter-observer variability documented in the assessment of tumor response classification in MPM30– 32 and on theoretical studies of mesothelioma growth according to non-spherical models.33 Armato et al. evaluated inter- and intra-observer variability in the manual measurement of tumor thickness on CT scans of 22 MPM patients; manual measurements were then compared with computer-generated measurements.30 The variability of measurements made by human observers had limits of agreements that spanned 30%, raising the possibility of erroneous indications of tumor change in the context of the RECIST guidelines. The variability observed in this study would probably be amplified if observers also had been asked to select independently the sections and measurements sites. In a subsequent study, observer variability in the measurement of temporal change in MPM tumor thickness and in the resulting tumor response classification was evaluated.31 An increase in the tumor response classification concor-
535
dance rate was obtained with a visual comparison approach relative to a written-report approach. The potential utility of semi-automated tumor thickness measurements was shown.31,32 Oxnard et al.33 evaluated the volumetric consistency of the modified RECIST response criteria as applied to geometric models simulating MPM growth (‘‘annulus’’, ‘‘lens’’ and ‘‘crescent’’ models). Application of the RECIST response criteria to MPM yielded PR and PD classifications based on smaller volume changes than for spherical tumors. This study demonstrates the weakness of the current modified RECIST criteria, which may result in over-classification of PR and PD. Furthermore, some morphological characteristics of MPM such as growth in the axial direction or along the lung fissures cannot be captured by any of the proposed CT-based response criteria. Therefore, alternative measurement modalities using direct measurement of tumor volume34,35 or metabolic imaging36 are being developed.
Time to disease progression as primary endpoint in MPM trials Considering the difficulties in assessing radiological response to therapy and the increasing use in clinical trials of cytostatic agents characterized by stabilization of the disease, the survival outcomes appear to remain the best treatment end points in MPM. In a combined analysis of three prospective trials performed by Fennell et al.,37 radiological responses did not appear to be correlated with survival improvement. In a phase II trial of the combination of pemetrexed and carboplatin as front-line treatment in patients with MPM, despite the apparently lower radiological response rate, time to progression (TTP) and overall survival (OS) were similar to the data reported with the standard combination of pemetrexed and cisplatin.38 Novel phase II studies using TTP as primary endpoint are being explored.21,39 A recent overview of the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer
Figure 1 Modified RECIST criteria for malignant pleural mesothelioma. Example of measurement of a single CT scan slice. Lines represent measurements of two sites perpendicular to fixed structure (chest wall and mediastinum).
536 Table 1
G.L. Ceresoli et al. Modified RECIST response criteria Definition
Complete response (CR)
Partial response (PR)
Disease progression (PD)
Stable disease (SD)
Disappearance of all target lesions with no evidence of tumor elsewhere Reduction of at least 30% in the total tumor measurement (sum of six unidimensional measurements, acquired in two positions at three separate levels on transverse cuts of CT scan) Increase of at least 20% in the total tumor measurement (as defined above) over the nadir measurement, or appearance of new lesions Disease meeting the criteria of neither PR nor PD
Group has pointed out that replacement of the response rate by TTP as the primary endpoint in future MPM phase II trials would allow a better selection of clinically active drugs.40 Ten mesothelioma trials with a total of 523 patients were evaluated; trials were grouped into three categories according to the published response rate: significant, moderate and insufficient clinical activity. Progression-free survival rate at fixed time-points (3, 4, 5 and 6 months) was calculated. These values have been proposed as reference values to design future phase II MPM trials (Table 2).
Evaluation of metabolic response FDG-PET is increasingly used for monitoring tumor response to chemotherapy and chemo-radiotherapy, and there is growing evidence that therapy-induced changes in tumor FDG uptake may predict response and patient outcome early in the course of therapy.41,42 In several neoplasms – such as lymphomas,43 gastrointestinal stromal tumors,44 esophageal cancer45 and non-small cell lung cancer46 – an early decline in FDG tumor uptake was mostly predictive of a subsequent response documented by standard CT or pathological assessment. More importantly, in some studies a significant correlation was found between metabolic response (MR) and patient outcome as measured by TTP or OS.46 A few pilot studies have explored the role of MR evaluated by FDGPET in patients with MPM treated with chemotherapy (Table 3). In these studies quantitative analysis was applied by computing SUV variations in areas of FDG accumulation at different time points during treatment (Fig. 2).41
Table 2
We have recently published the results of a prospective study of 22 MPM patients.47 FDG-PET was performed at baseline within the two weeks before initiation of chemotherapy and was repeated after 2 cycles of treatment. CT scan of chest and abdomen was performed at baseline and after every 2 cycles of chemotherapy and within a week of FDG-PET examination. A decrease of P25% in tumor FDG uptake as measured by the maximum value of SUV (SUVmax) was defined as a MR. This was in agreement with EORTC recommendations published in 1999.48 More recent reports have confirmed this cut-off in patients undergoing palliative chemotherapy for solid tumors.49 Best overall response from CT scans was determined according to hybrid uni- and bidimensional criteria.5,27 Four patients had a pleurodesis within 2 months of baseline PET scanning; because this could have influenced the baseline SUVmax values, patients without previous talc pleurodesis (indicated as the no-talc group) were also analyzed separately. Of the 20 patients who were assessable for early MR with FDG-PET, 8 (40%) were classified as responders and 12 (60%) as nonresponders. All the patients subsequently classified as responders according to radiological criteria had an early MR, and all the patients who showed disease progression at CT scan evaluation were metabolic non-responders. Patients classified as having SD had SUV changes distributed across a wide range of observations, ranging from 53% to +148%. Early MR showed a statistically significant correlation with patient time to progression (TTP): the median TTP for metabolic responders was 14 months versus 7 months for non-responders (P = 0.02). When the analysis was restricted to the no-talc group only, MR maintained a significant prognostic value (P = 0.01). On the contrary, no correlation was found between TTP and radiological response evaluated by CT in both overall (P = 0.57) and no-talc (P = 0.3) groups. Patients with a MR at early PET evaluation had a trend towards longer overall survival (P = 0.07). Other groups have reported similar observations.50–54 Flores et al.50 reported a statistically significant association between a decrease in FDG-PET SUV after chemotherapy and OS in 24 MPM patients treated with cisplatin-based induction chemotherapy and surgery. No quantitative cutoff was used to define MR. No difference in OS was observed in the same series according to CT response. In some other trials, different parameters taking the whole tumor volume into account were considered.51,52 However, despite its limitations, SUVmax appears to be a simple and reproducible approach to quantify tumor MR.41 Based on these studies, the use of FDG-PET for prediction of response and, more importantly, of survival outcomes appears promising and warrants validation in larger prospective series of MPM patients.55 Dynamic contrast-enhanced MRI (DCE-MRI) is another technique that is being used in oncology as an imaging
Progression-free survival (PFS) rates in MPM
Significant activity Moderate activity Poor activity
PFS rate, % (95% Confidence Intervals) 3 months 4 months
5 months
6 months
72% (64–80) 59% (50–67) 52% (46–58)
51% (42–60) 42% (33–50) 34% (28–40)
43% (34–51) 35% (27–43) 28% (23–34)
67% (59–75) 51% (43–60) 40% (34–46)
Modified from: Francart J et al. J Clin Oncol 2006;24:3007–3012 (Ref. 40).
Assessment of tumor response in malignant pleural mesothelioma Table 3
537
Metabolic response evaluation in MPM with FDG-PET
Author 47
Ceresoli et al. Flores et al.50 Steinert et al.51 Byrne et al.52 Kimura et al.53 Power et al.54
No. of pts
Chemotherapy
PET parameters
Findings
22 24 17 18 11 9
Pemetrexed-based Cisplatin-based Pemetrexed-based Cisplatin-gemcitabine Mainly cisplatin-based Pemetrexed-based
SUV SUV SUV, TLG SUV, TGV SUV SUV
MR predicts TTP MR predicts OS TLG more accurate than SUV TGV predicts TTP MR observed in lesions with PR or SD at CT scan No correlation with CT response
Modified from: Ceresoli et al. J Clin Oncol 2006;24:4587–4593 (Ref. 47). PET: positron emission tomography; CT: computed tomography; SUV: standardized uptake value; TLG: total lesion glycolysis; TGV: total glycolytic volume; MR: metabolic response; PR: partial response; SD: stable disease; TTP: time to progression; OS: overall survival.
Figure 2
PET axial slices before and after treatment are shown in the upper and lower panels.
biomarker. DCE-MRI measures parameters of tissue microvasculature and is a promising method for characterizing tumor response to antiangiogenic treatments.56 In a feasibility study conducted on 19 patients with a diagnosis of MPM, scheduled to receive chemotherapy with gemcitabine, DCE-MRI was performed before and after treatment with the aim of differentiating benign from malignant tissue and comparing pharmacokinetic with clinical parameters and survival.57 Normal and tumor tissue could be distinguished by the pharmacokinetic parameters amplitude (Amp) and elimination rate constant (kel). Clinical responders had a lower redistribution rate constant (kep); the median kep value within the tumor was 2.6 min for responders in comparison to 3.6 min for non-responders; this parameter was associated with patient survival. DCE-MRI has several practical limitations, due to the lack of standardization
and to the need for strict adherence to technical specifications which can differ by disease site and therapeutic strategy.56 However, preliminary results are encouraging and warrant further studies including this methodology and pharmacokinetic analysis to assess MPM.
Functional and quality of life - related endpoints MPM is a highly symptomatic malignancy. Accurate evaluation of the impact of this disease and its treatments on symptoms and health-related quality of life (HRQoL) is an important goal.58–60 There are no specific HRQoL tools for MPM patients. Recently, a modified version of the Lung Cancer Symptom Scale (LCSS), an instrument used to assess
538 HRQoL in patients with lung cancer, was incorporated in two clinical trials of pemetrexed in patients with MPM.61,62 Furthermore, the LCSS-Meso appeared a feasible and valid method, with high patient and staff acceptance, in a large multinational trial of pemetrexed/cisplatin versus cisplatin alone; in this trial, in addition to survival advantage, the combination regimen was associated with a significant improvement in HRQoL and symptom relief when compared with cisplatin alone.63 Other studies have shown the feasibility and validity of using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-30) and Lung Cancer Module (QLQ-LC13) in patients with MPM undergoing chemotherapy.60,64 Dyspnea is one of the most common symptoms of restrictive lung function associated with MPM. Pulmonary function tests (PFTs) are the most commonly used indicators of changes in lung function. Forced vital capacity changes over the course of treatment were significantly correlated with radiologic response according to modified RECIST criteria in 73 patients entered in two clinical trials of cisplatin/gemcitabine in MPM.29 Paoletti et al.65 reported on changes in several functional parameters (slow vital capacity, forced vital capacity and forced expiratory volume in one second) in patients treated in the phase III study of pemetrexed/cisplatin versus cisplatin. Responders in both treatment groups had a significant improvement in PFTs in comparison to patients with SD; in addition, patients with SD had better PFTs than patients with PD. This may be clinically relevant because patients with no objective tumor response can have symptomatic improvement. More recently, two-dimensional and three-dimensional dynamic MRI was used to monitor lung motion in patients with MPM before and after chemotherapy.66 Maximum craniocaudal lung dimensions and lung volumes were monitored in 22 patients, separated into the tumor-bearing and nontumor-bearing hemithorax. Vital capacity was measured for comparison using spirometry. Dynamic MRI was capable of detecting changes in lung motion and volumetry not detected by spirometry, and is proposed by the authors as a further measure of therapy response.
Serum markers The difficulties in assessing radiological response to therapy in MPM, and the large variations of the prognostic factors identified so far,67,68 make the potential availability of serum tumor markers very useful. Small studies on a limited number of MPM patients have evaluated retrospectively the prognostic and predictive value of hyaluronic acid69 and of the cytokeratin tumor markers TPA (Tissue Polypeptide Antigen) and Cyfra 21-1 (an assay specific for the determination of fragment 19),70 with inconsistent results. Recently, two molecules (mesothelin and osteopontin) have been studied in serum samples from a large number of MPM patients.71,72 Mesothelin is a glycoprotein attached to the cell surface; it is not a cancer-specific antigen but it is a differentiation antigen thought to have a role in cell adhesion and in cellto-cell recognition and signaling. It is over-expressed in several human tumors such as mesothelioma, pancreatic cancer and ovarian cancer.73 Mesothelin gene encodes a
G.L. Ceresoli et al. precursor which forms two proteins, the membrane-bound mesothelin and a soluble protein. Other related soluble molecules have been identified; all these soluble mesothelin-related proteins (SMRP) are detectable by a single ELISA assay.74 Robinson et al.71 evaluated SMRP concentrations of serum samples from 44 MPM as compared to 228 controls (68 matched healthy controls, 40 of whom had proven exposure to asbestos, and 160 patients with other inflammatory or malignant lung and pleural diseases). The assay had a sensitivity of 84% for mesothelioma, 37 of 44 patients being detected, and high specificity. Patients with epithelial MPM and larger tumors had higher concentrations of SMRP than those with sarcomatoid histotype and smaller tumor size. In patients for whom serum samples were available at different time points, a trend towards increasing SMRP concentrations with disease progression was observed, while SMRP levels fell after debulking surgery. These early data suggest a possible role of SMRP determination in monitoring response to different therapeutic interventions. Osteopontin is a glycoprotein that is overexpressed in several human tumors such as lung, breast and colon cancer.75,76 Osteopontin mediates cell–matrix interactions; high levels of this molecule correlate with tumor invasion, progression and metastasis. Its expression is regulated by pathways that are associated with asbestos-induced carcinogenesis.77 Pass et al.72 investigated the role of osteopontin in MPM, measuring serum levels of this molecule in 76 patients with MPM and in 114 controls (69 subjects with asbestos exposure and 45 subjects who were not exposed to asbestos). Serum osteopontin levels, detected with an ELISA assay, were significantly higher in patients with MPM, with a sensitivity of 77.6% and a specificity of 85.5%. There were no significant differences in mean serum osteopontin levels among patients with stage I, II or III MPM. Prospective studies with serum osteopontin measurements at different time points are needed to determine the role of this marker in monitoring response to therapy of MPM.
Conclusions Assessment of response with criteria based on CT measurements is challenging in MPM, due to its pattern of growth. Modified RECIST criteria remain the standard methodology of response evaluation, even though modeling of MPM growth challenges the use of PR and PD classifications of the standard RECIST in this disease. Careful consideration must be given to the measurement acquisition process to minimize inter-observer variability. Functional and quality of life parameters remain valuable endpoints in monitoring MPM. In the future, computer-assisted techniques for CT measurement, metabolic imaging with DCE-MRI and FDGPET and use of new serum markers may play a role in assessing response to treatment in this disease.
Conflict of interest statement None declared.
References 1. Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591–603.
Assessment of tumor response in malignant pleural mesothelioma 2. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117:54–65. 3. Robinson BWS, Musk AW, Lake AR. Malignant mesothelioma. Lancet 2005;366:397–408. 4. Ellis P, Davies AM, Evans WK, et al. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. J Thorac Oncol 2006;1:591–601. 5. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–44. 6. Van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organization for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 2005;23:6881–9. 7. Zucali PA, Giaccone G. Biology and management of malignant pleural mesothelioma. Eur J Cancer 2006;42:2706–14. 8. Scagliotti GV, Selvaggi G. Emerging drugs for mesothelioma. Expert Opin Emerging Drugs 2007;12:127–37. 9. Metintas M, Ucgung I, Elbek O, et al. Computer tomography features in malignant pleural mesothelioma and other commonly seen pleural diseases. Eur J Radiol 2002;41:1–9. 10. Marom EM, Erasmus JJ, Pass HI, Patz Jr EF. The role of imaging in malignant pleural mesothelioma. Semin Oncol 2002;29:26–35. 11. Ng CS, Munden RF, Libshitz HI. Malignant pleural mesothelioma: the spectrum of manifestations on CT in 70 cases. Clin Radiol 1999;54:415–21. 12. Heelan RT, Rusch VW, Begg CB, Panicek DM, Caravelli JF, Eisen C. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. Am J Roentgenol 1999;172:1039–46. 13. Hierholzer J, Luo L, Bittner RC, et al. MRI and CT in the differential diagnosis of pleural disease. Chest 2000;118: 604–9. 14. Edwards JG, Stewart DJ, Martin-Ucar A, Muller S, Richard C, Waller DA. The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg 2006;131: 981–7. 15. Carretta A, Landoni C, Melloni G, et al. 18-FDG positron emission tomography in the evaluation of malignant pleural diseases – a pilot study. Eur J Cardiothorac Surg 2000;17: 377–83. 16. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2003;126:11–6. 17. Erasmus JJ, Truong MT, Smythe WR, et al. Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: staging implications. J Thorac Cardiovasc Surg 2005;129: 1364–70. 18. Truong MT, Marom EM, Erasmus JJ. Preoperative evaluation of patients with malignant pleural mesothelioma: role of integrated CT-PET imaging. J Thorac Imaging 2006;21:146–53. 19. Flores RM, Akhurst T, Gonen M, et al. Positron emission tomography predicts survival in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2006;132:763–8. 20. Nowak AK. CT, RECIST, and malignant pleural mesothelioma. Lung Cancer 2005;49(Suppl. 1):S37–40. 21. Nowak AK. Phase II trials in mesothelioma: an increasing challenge. Lung Cancer 2005;50:87–90.
539
22. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14. 23. Solheim OP, Saeter G, Finnanger AM, Stenwig AE. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. Br J Cancer 1992;65:956–60. 24. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. 25. Van Klaveren RJ, Aerts JGJV, De Bruin H, Giaccone G, Manegold JP, Van Meerbeeck JP. Inadequacy of the RECIST criteria for response evaluation in patients with malignant pleural mesothelioma. Lung Cancer 2004;43:63–9. 26. Monetti F, Casanova S, Grasso A, Cafferata MA, Ardizzoni A, Neumaier CE. Inadequacy of the new response evaluation criteria in solid tumors (RECIST) in patients with malignant pleural mesothelioma: report of four cases. Lung Cancer 2004;43:71–4. 27. Byrne MJ, Davidson JA, Musk AW, et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999;17:25–30. 28. Hazarika M, White RM, Booth BP, et al. Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 2005;11: 982–92. 29. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15:257–60. 30. Armato III SG, Oxnard GR, MacMahon H, et al. Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques. Med Phys 2004;31: 1105–15. 31. Armato III SG, Ogarek JL, Starkey A, et al. Variability in mesothelioma tumor response classification. AJR 2006;186: 1000–6. 32. Armato III SG, Oxnard GR, Kocherginsky M, Vogelzang NJ, Kindler HL, MacMahon H. Evaluation of semiautomated measurements of mesothelioma tumor thickness on CT scans. Acad Radiol 2005;12:1301–9. 33. Oxnard GR, Armato III SG, Kindler HL. Modeling of mesothelioma growth demonstrates weakness of current response criteria. Lung Cancer 2006;52:141–8. 34. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998;115:310–7. 35. Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpem EF, Sumher JE. CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques – initial observations. Radiology 2002;225:416–9. 36. Atri M. New technologies and directed agents for applications of cancer imaging. J Clin Oncol 2006;24:3299–308. 37. Fennell D, Steele J, Sheaff M, et al. Response of malignant pleural mesothelioma to chemotherapy does not confer a survival advantage. Lung Cancer 2005;49(Suppl. 2):S220. [abstr. P-397]. 38. Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443–8. 39. Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control Clin Trials 2000;21:343–59. 40. Francart J, Legrand C, Sylvester R, Van Glabbeke M, Van Meerbeeck JP, Robert A. Progression-free survival rate as primary endpoint for phase II cancer clinical trials: application to mesothelioma. The EORTC Lung Cancer Group. J Clin Oncol 2006;24:3007–12. 41. Weber WA. Use of PET for monitoring cancer therapy and for predicting outcome. J Nucl Med 2005;46:983–95.
540 42. Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. New Engl J Med 2006;354: 496–507. 43. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with 18F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002;13:1356–63. 44. Goerres GW, Stupp R, Barghouth G, et al. The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate. Eur J Nucl Med Mol Imaging 2005;32:153–62. 45. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19:3058–65. 46. Weber WA, Petersen V, Schmidt B, et al. Positron emission tomography in non-small cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol 2003;21:2651–7. 47. Ceresoli GL, Chiti A, Zucali PA, et al. Early evaluation in malignant pleural mesothelioma by positron emission tomography with [18F] fluorodeoxyglucose. J Clin Oncol 2006;24: 4587–93. 48. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer 1999;35:1773–82. 49. Weber WA, Wieder H. Monitoring chemotherapy and radiotherapy of solid tumors. Eur J Nucl Med Mol Imaging 2006;33(Suppl. 13):S27–37. 50. Flores RM, Akhurst T, Krug L, et al. Decreased PET SUV after induction chemotherapy is associated with improved survival in malignant pleural mesothelioma (MPM). Proc Am Soc Clin Oncol 2005;23:636S. [abstr 3690]. 51. Steinert HC, Santos Dellea MM, Burger C, et al. Therapy response evaluation in malignant pleural mesothelioma with integrated PET-CT imaging. Lung Cancer 2005;49(Suppl. 1): S33–5. 52. Byrne M, Francis R, Van der Schaaf A, et al. Comparison of FDG-PET and CT scans to assess response to chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer 2005;49(Suppl. 2):S220. [abstr. O-074]. 53. Kimura T, Yoshimura N, Mitsuoka S, et al. Monitoring of chemotherapy response in multiple disseminated malignant pleural mesothelioma using fluorodeoxyglucose positron emission tomography. Proc Am Soc Clin Oncol 2005;23:664S. [abstr. 7177]. 54. Power D, Murphy C, Farrelly C, et al. Prediction of response to chemotherapy in malignant pleural mesothelioma: early positron emission tomography versus computed tomography. Lung Cancer 2005;49(Suppl. 2):S227. [abstr. P-424]. 55. Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol 2006;24:3282–92. 56. Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol 2006;24: 3293–8. 57. Giesel FL, Bischoff H, Von Tengg-Kobligk H, et al. Dynamic contrast-enhanced MRI of malignant pleural mesothelioma. A feasibility study of noninvasive assessment, therapeutic followup, and possible predictor of improved outcome. Chest 2006;129:1570–6. 58. Steele JPC, Shamash J, Evans MT, et al. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 2000;18:3912–7. 59. Andreopoulou E, Ross PJ, O’Brien MER, et al. The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma. Ann Oncol 2004;15:1406–12.
G.L. Ceresoli et al. 60. Muers MF, Rudd RM, O’Brien MER, et al. BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112. Thorax 2004;59:144–8. 61. Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Adapting the Lung Cancer Symptom Scale (LCSS) to mesothelioma. Using the LCSS-Meso conceptual model for validation. Cancer 2004;101:587–95. 62. Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Measuring quality of life in patients with pleural mesothelioma using a modified version of the Lung Cancer Symptom Scale (LCSS): psychometric properties of the LCSS-Meso. Support Care Cancer 2006;14:11–21. 63. Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: results of the randomized pemetrexed+cisplatin vs. cisplatin trial using the LCSS-Meso instrument. Proc Am Soc Clin Oncol 2003;22. [abstr 7177]. 64. Nowak AK, Stockler MR, Byrne MJ. Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire and Lung Cancer module. J Clin Oncol 2004;22:3172–80. 65. Paoletti P, Pistolesi M, Rusthoven JJ, et al. Correlation of pulmonary function tests with best tumor response status: results from the phase III study of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma. Proc Am Soc Clin Oncol 2003;22. [abstr. 2651]. 66. Plathow C, Klopp M, Schoebinger M, et al. Monitoring of lung motion in patients with malignant pleural mesothelioma using two-dimensional and three-dimensional dynamic magnetic resonance imaging. Comparison with spirometry. Invest Radiol 2006;41:443–8. 67. Curran D, Sahmoud T, Therasse P, Van Meerbeeck J, Postmus G, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998;16: 145–52. 68. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998;113:723– 31. 69. Frebourg T, Lerebours G, Delpech B, et al. Serum hyaluronate in malignant pleural mesothelioma. Cancer 1987;59: 2104–7. 70. Schouwink H, Korse CM, Bonfrer JMG, Haart AA, Baas P. Prognostic value of the serum markers Cyfra 21-1 and tissue polypeptide antigen in malignant mesothelioma. Lung Cancer 1999;25:25–32. 71. Robinson BWS, Creaney J, Lake R, et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612–6. 72. Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. New Engl J Med 2005;353:1564–73. 73. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancer. PNAS 1996;93:136–40. 74. Scholler N, Fu N, Yang Y, et al. Soluble members of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. PNAS 1999;96:11531–6. 75. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7: 4060–6.
Assessment of tumor response in malignant pleural mesothelioma 76. Martinetti A, Bajetta E, Ferrari L, et al. Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrazole. Endocr Relat Cancer 2004;11:771–9.
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77. Sandhu H, Dehnen W, Roller M, Abel J, Unfried K. mRNA expression patterns in different stages of asbestos-induced carcinogenesis in rats. Carcinogenesis 2000;21:1023–9.
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CONTROVERSY
Assessment of tumor response in malignant pleural mesothelioma Giovanni L. Ceresoli a,*, Arturo Chiti b, Paolo A. Zucali a, Federico Cappuzzo a, Fabio De Vincenzo a, Raffaele Cavina a, Marcello Rodari b, Dario Poretti c, Fabio Romano Lutman c, Armando Santoro a a b c
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy Department of Nuclear Medicine, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy Department of Radiology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
Received 13 June 2007; received in revised form 17 July 2007; accepted 25 July 2007
KEYWORDS Mesothelioma; Response evaluation; CT scan; PET; Serum markers
Summary Most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of their disease. Assessment of the response with conventional criteria based on computed tomography (CT) measurements is challenging, due to the circumferential and axial pattern of growth of MPM. Such difficulties hinder an accurate evaluation of clinical study results and make the clinical management of patients critical. Several radiological response systems have been proposed, but neither WHO criteria nor the more recent RECIST unidimensional criteria nor hybrid uni- and bidimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria for MPM have been published. Although they are already being used in current clinical trials, they have been criticized based on the high grade of inter-observer variability and on theoretical studies of mesothelioma growth according to non-spherical models. Computer-assisted techniques for CT measurement are being developed. The use of FDG-PET for prediction of response and, more importantly, of survival outcomes of MPM patients is promising and warrants validation in large prospective series. New serum markers such as osteopontin and mesothelin-related proteins are under evaluation and in the future might play a role in assessing the response of MPM to treatment. c 2007 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +39 02 82244080; fax: +39 02 82244590. E-mail addresses: [email protected] (G.L. Ceresoli), [email protected] (A. Chiti), [email protected] (P.A. Zucali), [email protected] (F. Cappuzzo), [email protected] (F. De Vincenzo), raffaele.cavina@ humanitas.it (R. Cavina), [email protected] (M. Rodari), [email protected] (D. Poretti), [email protected] (F.R. Lutman), [email protected] (A. Santoro).
0305-7372/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2007.07.012
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Introduction Malignant pleural mesothelioma (MPM) is an aggressive tumor which usually has a poor prognosis. Its incidence is increasing throughout most of the world, and it is predicted that it will rise in the next 10–15 years as a result of widespread exposure to asbestos in past decades.1 The management of patients with MPM remains controversial. Due to the usually advanced stage at presentation, only a minority of patients are eligible for radical surgery2; most are candidates for chemotherapy during the course of their disease. The relatively low incidence of the disease has made it difficult to conduct randomized controlled studies with adequate numbers of cases. Therefore, a nihilistic attitude has existed for many years regarding treatment of MPM, with retrospective studies reporting median survival of less than one year and 5-year survival rates of 1% or less.3 Several new cytotoxic agents with definite activity in mesothelioma have been evaluated in the last decade, including gemcitabine, vinorelbine and the antifolates pemetrexed and raltitrexed.4 Recently, two randomized controlled trials wherein single-agent cisplatin was compared with its combination with an antifolate have established the combination treatment as the reference regimen for first-line chemotherapy.5,6 More specifically, a large phase III trial testing pemetrexed and cisplatin versus cisplatin alone in 448 chemotherapy-naive patients with MPM showed a significant advantage with the combined regimen in survival, time to progression and response rate.5 Several biological agents have been explored or are currently under evaluation.7,8 Contrast-enhanced computed tomography (CT) is the primary imaging modality for the evaluation of MPM; rind-like extension of the tumor on the pleural surfaces is the most common CT feature, and is seen in up to 70% of cases.9–11 However, it lacks the ability to depict the extent of disease accurately. For patients being assessed for surgery, magnetic resonance imaging (MRI) can provide additional information in detecting chest wall and diaphragmatic invasion.12,13 On the other hand, the sensitivity and specificity of CT for mediastinal nodal involvement are very low, due to the unpredictable and not well characterized lymphatic pattern of spread of MPM.14 The use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of MPM has been described recently. FDG-PET has proved useful in detecting malignant pleural lesions15 and partially in assessing the extent of tumor involvement. In one study of 65 MPM patients, this imaging technique correctly detected extrathoracic metastases but failed to reliably identify the locoregional (tumor and mediastinal nodal) status of MPM16; sensitivity was 19% for locally advanced disease (T4) and 11% for nodal metastases. Integrated CTPET with coregistration of anatomic and functional imaging data increases the accuracy of MPM staging for T4 disease (sensitivity 67%, specificity 93%), while it remains inaccurate in the evaluation of nodal metastases (sensitivity 38%, specificity 78%), with high rates of false-positive and false-negative results.17,18 Further studies have demonstrated that FDG uptake, measured at diagnosis by standardized uptake value (SUV), has independent prognostic value in this disease. In a retrospective study of 137 patients with MPM, a SUV > 10 was significantly related to poor prognosis in multivariate analysis; patients with high SUV had a
G.L. Ceresoli et al. death hazard ratio of 1.9 compared to patients with SUV <10.19
CT-Based assessment of response: WHO, RECIST, new proposals Assessment of response with conventional criteria based on CT measurements is challenging in MPM, due to its circumferential and axial pattern of growth. Multiple thoracic levels may be involved; while there are anatomical landmarks in the upper and mid thorax, in the lower thorax there are few landmarks where levels of measurement can be reproducibly identified.20 Such difficulties hinder an accurate evaluation of clinical study results, particularly in phase II trials,21 and make the clinical management of patients critical. However, the recent development of more active regimens underlines the need for accurate techniques for evaluating response in this disease. Several response criteria have been proposed.20 In 1981, the World Health Organization (WHO) established the first quantitative criteria for measurement of solid tumors on imaging studies before and after chemotherapy.22 According to these response criteria, based on measurement of bidimensional lesions, a partial response (PR) was defined by a P50% decrease in the sum of the products of the longest diameter of each lesion and its perpendicular diameter; an increase of P25% of this sum was defined as progressive disease (PD). These criteria were poorly suited to the growth pattern of MPM. In early chemotherapy trials the need for ‘‘ad hoc’’ methods of evaluation was reported, and the introduction of unidimensional measurements was proposed.23 The RECIST criteria (Response Evaluation Criteria in Solid Tumors), which are widely used in clinical trials involving other solid tumors, use only unidimensional measurements of the longest diameter of the lesions.24 According to RECIST criteria, PR is defined by a P30% decrease in the sum of unidimensional measurements of target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, can be measured. PD is defined by a P20% increase of this sum. This approach is based on mathematical calculations of the volume changes of roughly spherical tumors, and therefore is poorly applicable to non-spherical tumors such as MPM. In MPM it is nearly impossible to establish which lesions should be considered as ‘‘target’’ or ‘‘nontarget’’, or to measure the longest diameter of the tumor. Van Klaveren et al.,25 in a series of 34 patients treated with chemotherapy, found very poor agreement between response evaluations according to WHO and RECIST criteria, with RECIST underscoring the tumor response and the tumor progression in most of cases; the percentage of patients in whom one or more discrepancies were detected was 47%. Similar results were reported by Monetti et al.26 in a more limited series of MPM patients. Hybrid uni- and bidimensional criteria have been proposed by other authors27 and used in other large trials, in particular in the landmark phase III trial of the combination of pemetrexed/cisplatin versus cisplatin alone.5 However, considerable discrepancy was reported among study investigators and independent reviewers in the evaluation of patients treated in this trial where tumor response could be confirmed in only half of
Assessment of tumor response in malignant pleural mesothelioma patients.28 Recently, modified RECIST criteria have been developed and validated by Byrne and Nowak.29 A total of 73 patients from two clinical trials of cisplatin/gemcitabine in MPM were reviewed. Tumor thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on transverse CT slices (Fig. 1); levels were at least 1 cm apart and related to anatomical landmarks to allow reproducible assessment at later time points. Bidimensionally measurable lesions, such as mediastinal lymph nodes, were recorded unidimensionally as for RECIST. The sum of the six measurements defined a pleural unidimensional measure. Criteria for PR and PD were the same as in the original RECIST system (Table 1). The response according to these modified RECIST criteria predicted longer patient survival (15.1 versus 8.9 months, P = 0.03) and improved respiratory function, with an increase of forced vital capacity during treatment (P < 0.0001). Although modified RECIST criteria are being used in most current clinical trials, they have been criticized based on the high grade of inter-observer variability documented in the assessment of tumor response classification in MPM30– 32 and on theoretical studies of mesothelioma growth according to non-spherical models.33 Armato et al. evaluated inter- and intra-observer variability in the manual measurement of tumor thickness on CT scans of 22 MPM patients; manual measurements were then compared with computer-generated measurements.30 The variability of measurements made by human observers had limits of agreements that spanned 30%, raising the possibility of erroneous indications of tumor change in the context of the RECIST guidelines. The variability observed in this study would probably be amplified if observers also had been asked to select independently the sections and measurements sites. In a subsequent study, observer variability in the measurement of temporal change in MPM tumor thickness and in the resulting tumor response classification was evaluated.31 An increase in the tumor response classification concor-
535
dance rate was obtained with a visual comparison approach relative to a written-report approach. The potential utility of semi-automated tumor thickness measurements was shown.31,32 Oxnard et al.33 evaluated the volumetric consistency of the modified RECIST response criteria as applied to geometric models simulating MPM growth (‘‘annulus’’, ‘‘lens’’ and ‘‘crescent’’ models). Application of the RECIST response criteria to MPM yielded PR and PD classifications based on smaller volume changes than for spherical tumors. This study demonstrates the weakness of the current modified RECIST criteria, which may result in over-classification of PR and PD. Furthermore, some morphological characteristics of MPM such as growth in the axial direction or along the lung fissures cannot be captured by any of the proposed CT-based response criteria. Therefore, alternative measurement modalities using direct measurement of tumor volume34,35 or metabolic imaging36 are being developed.
Time to disease progression as primary endpoint in MPM trials Considering the difficulties in assessing radiological response to therapy and the increasing use in clinical trials of cytostatic agents characterized by stabilization of the disease, the survival outcomes appear to remain the best treatment end points in MPM. In a combined analysis of three prospective trials performed by Fennell et al.,37 radiological responses did not appear to be correlated with survival improvement. In a phase II trial of the combination of pemetrexed and carboplatin as front-line treatment in patients with MPM, despite the apparently lower radiological response rate, time to progression (TTP) and overall survival (OS) were similar to the data reported with the standard combination of pemetrexed and cisplatin.38 Novel phase II studies using TTP as primary endpoint are being explored.21,39 A recent overview of the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer
Figure 1 Modified RECIST criteria for malignant pleural mesothelioma. Example of measurement of a single CT scan slice. Lines represent measurements of two sites perpendicular to fixed structure (chest wall and mediastinum).
536 Table 1
G.L. Ceresoli et al. Modified RECIST response criteria Definition
Complete response (CR)
Partial response (PR)
Disease progression (PD)
Stable disease (SD)
Disappearance of all target lesions with no evidence of tumor elsewhere Reduction of at least 30% in the total tumor measurement (sum of six unidimensional measurements, acquired in two positions at three separate levels on transverse cuts of CT scan) Increase of at least 20% in the total tumor measurement (as defined above) over the nadir measurement, or appearance of new lesions Disease meeting the criteria of neither PR nor PD
Group has pointed out that replacement of the response rate by TTP as the primary endpoint in future MPM phase II trials would allow a better selection of clinically active drugs.40 Ten mesothelioma trials with a total of 523 patients were evaluated; trials were grouped into three categories according to the published response rate: significant, moderate and insufficient clinical activity. Progression-free survival rate at fixed time-points (3, 4, 5 and 6 months) was calculated. These values have been proposed as reference values to design future phase II MPM trials (Table 2).
Evaluation of metabolic response FDG-PET is increasingly used for monitoring tumor response to chemotherapy and chemo-radiotherapy, and there is growing evidence that therapy-induced changes in tumor FDG uptake may predict response and patient outcome early in the course of therapy.41,42 In several neoplasms – such as lymphomas,43 gastrointestinal stromal tumors,44 esophageal cancer45 and non-small cell lung cancer46 – an early decline in FDG tumor uptake was mostly predictive of a subsequent response documented by standard CT or pathological assessment. More importantly, in some studies a significant correlation was found between metabolic response (MR) and patient outcome as measured by TTP or OS.46 A few pilot studies have explored the role of MR evaluated by FDGPET in patients with MPM treated with chemotherapy (Table 3). In these studies quantitative analysis was applied by computing SUV variations in areas of FDG accumulation at different time points during treatment (Fig. 2).41
Table 2
We have recently published the results of a prospective study of 22 MPM patients.47 FDG-PET was performed at baseline within the two weeks before initiation of chemotherapy and was repeated after 2 cycles of treatment. CT scan of chest and abdomen was performed at baseline and after every 2 cycles of chemotherapy and within a week of FDG-PET examination. A decrease of P25% in tumor FDG uptake as measured by the maximum value of SUV (SUVmax) was defined as a MR. This was in agreement with EORTC recommendations published in 1999.48 More recent reports have confirmed this cut-off in patients undergoing palliative chemotherapy for solid tumors.49 Best overall response from CT scans was determined according to hybrid uni- and bidimensional criteria.5,27 Four patients had a pleurodesis within 2 months of baseline PET scanning; because this could have influenced the baseline SUVmax values, patients without previous talc pleurodesis (indicated as the no-talc group) were also analyzed separately. Of the 20 patients who were assessable for early MR with FDG-PET, 8 (40%) were classified as responders and 12 (60%) as nonresponders. All the patients subsequently classified as responders according to radiological criteria had an early MR, and all the patients who showed disease progression at CT scan evaluation were metabolic non-responders. Patients classified as having SD had SUV changes distributed across a wide range of observations, ranging from 53% to +148%. Early MR showed a statistically significant correlation with patient time to progression (TTP): the median TTP for metabolic responders was 14 months versus 7 months for non-responders (P = 0.02). When the analysis was restricted to the no-talc group only, MR maintained a significant prognostic value (P = 0.01). On the contrary, no correlation was found between TTP and radiological response evaluated by CT in both overall (P = 0.57) and no-talc (P = 0.3) groups. Patients with a MR at early PET evaluation had a trend towards longer overall survival (P = 0.07). Other groups have reported similar observations.50–54 Flores et al.50 reported a statistically significant association between a decrease in FDG-PET SUV after chemotherapy and OS in 24 MPM patients treated with cisplatin-based induction chemotherapy and surgery. No quantitative cutoff was used to define MR. No difference in OS was observed in the same series according to CT response. In some other trials, different parameters taking the whole tumor volume into account were considered.51,52 However, despite its limitations, SUVmax appears to be a simple and reproducible approach to quantify tumor MR.41 Based on these studies, the use of FDG-PET for prediction of response and, more importantly, of survival outcomes appears promising and warrants validation in larger prospective series of MPM patients.55 Dynamic contrast-enhanced MRI (DCE-MRI) is another technique that is being used in oncology as an imaging
Progression-free survival (PFS) rates in MPM
Significant activity Moderate activity Poor activity
PFS rate, % (95% Confidence Intervals) 3 months 4 months
5 months
6 months
72% (64–80) 59% (50–67) 52% (46–58)
51% (42–60) 42% (33–50) 34% (28–40)
43% (34–51) 35% (27–43) 28% (23–34)
67% (59–75) 51% (43–60) 40% (34–46)
Modified from: Francart J et al. J Clin Oncol 2006;24:3007–3012 (Ref. 40).
Assessment of tumor response in malignant pleural mesothelioma Table 3
537
Metabolic response evaluation in MPM with FDG-PET
Author 47
Ceresoli et al. Flores et al.50 Steinert et al.51 Byrne et al.52 Kimura et al.53 Power et al.54
No. of pts
Chemotherapy
PET parameters
Findings
22 24 17 18 11 9
Pemetrexed-based Cisplatin-based Pemetrexed-based Cisplatin-gemcitabine Mainly cisplatin-based Pemetrexed-based
SUV SUV SUV, TLG SUV, TGV SUV SUV
MR predicts TTP MR predicts OS TLG more accurate than SUV TGV predicts TTP MR observed in lesions with PR or SD at CT scan No correlation with CT response
Modified from: Ceresoli et al. J Clin Oncol 2006;24:4587–4593 (Ref. 47). PET: positron emission tomography; CT: computed tomography; SUV: standardized uptake value; TLG: total lesion glycolysis; TGV: total glycolytic volume; MR: metabolic response; PR: partial response; SD: stable disease; TTP: time to progression; OS: overall survival.
Figure 2
PET axial slices before and after treatment are shown in the upper and lower panels.
biomarker. DCE-MRI measures parameters of tissue microvasculature and is a promising method for characterizing tumor response to antiangiogenic treatments.56 In a feasibility study conducted on 19 patients with a diagnosis of MPM, scheduled to receive chemotherapy with gemcitabine, DCE-MRI was performed before and after treatment with the aim of differentiating benign from malignant tissue and comparing pharmacokinetic with clinical parameters and survival.57 Normal and tumor tissue could be distinguished by the pharmacokinetic parameters amplitude (Amp) and elimination rate constant (kel). Clinical responders had a lower redistribution rate constant (kep); the median kep value within the tumor was 2.6 min for responders in comparison to 3.6 min for non-responders; this parameter was associated with patient survival. DCE-MRI has several practical limitations, due to the lack of standardization
and to the need for strict adherence to technical specifications which can differ by disease site and therapeutic strategy.56 However, preliminary results are encouraging and warrant further studies including this methodology and pharmacokinetic analysis to assess MPM.
Functional and quality of life - related endpoints MPM is a highly symptomatic malignancy. Accurate evaluation of the impact of this disease and its treatments on symptoms and health-related quality of life (HRQoL) is an important goal.58–60 There are no specific HRQoL tools for MPM patients. Recently, a modified version of the Lung Cancer Symptom Scale (LCSS), an instrument used to assess
538 HRQoL in patients with lung cancer, was incorporated in two clinical trials of pemetrexed in patients with MPM.61,62 Furthermore, the LCSS-Meso appeared a feasible and valid method, with high patient and staff acceptance, in a large multinational trial of pemetrexed/cisplatin versus cisplatin alone; in this trial, in addition to survival advantage, the combination regimen was associated with a significant improvement in HRQoL and symptom relief when compared with cisplatin alone.63 Other studies have shown the feasibility and validity of using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-30) and Lung Cancer Module (QLQ-LC13) in patients with MPM undergoing chemotherapy.60,64 Dyspnea is one of the most common symptoms of restrictive lung function associated with MPM. Pulmonary function tests (PFTs) are the most commonly used indicators of changes in lung function. Forced vital capacity changes over the course of treatment were significantly correlated with radiologic response according to modified RECIST criteria in 73 patients entered in two clinical trials of cisplatin/gemcitabine in MPM.29 Paoletti et al.65 reported on changes in several functional parameters (slow vital capacity, forced vital capacity and forced expiratory volume in one second) in patients treated in the phase III study of pemetrexed/cisplatin versus cisplatin. Responders in both treatment groups had a significant improvement in PFTs in comparison to patients with SD; in addition, patients with SD had better PFTs than patients with PD. This may be clinically relevant because patients with no objective tumor response can have symptomatic improvement. More recently, two-dimensional and three-dimensional dynamic MRI was used to monitor lung motion in patients with MPM before and after chemotherapy.66 Maximum craniocaudal lung dimensions and lung volumes were monitored in 22 patients, separated into the tumor-bearing and nontumor-bearing hemithorax. Vital capacity was measured for comparison using spirometry. Dynamic MRI was capable of detecting changes in lung motion and volumetry not detected by spirometry, and is proposed by the authors as a further measure of therapy response.
Serum markers The difficulties in assessing radiological response to therapy in MPM, and the large variations of the prognostic factors identified so far,67,68 make the potential availability of serum tumor markers very useful. Small studies on a limited number of MPM patients have evaluated retrospectively the prognostic and predictive value of hyaluronic acid69 and of the cytokeratin tumor markers TPA (Tissue Polypeptide Antigen) and Cyfra 21-1 (an assay specific for the determination of fragment 19),70 with inconsistent results. Recently, two molecules (mesothelin and osteopontin) have been studied in serum samples from a large number of MPM patients.71,72 Mesothelin is a glycoprotein attached to the cell surface; it is not a cancer-specific antigen but it is a differentiation antigen thought to have a role in cell adhesion and in cellto-cell recognition and signaling. It is over-expressed in several human tumors such as mesothelioma, pancreatic cancer and ovarian cancer.73 Mesothelin gene encodes a
G.L. Ceresoli et al. precursor which forms two proteins, the membrane-bound mesothelin and a soluble protein. Other related soluble molecules have been identified; all these soluble mesothelin-related proteins (SMRP) are detectable by a single ELISA assay.74 Robinson et al.71 evaluated SMRP concentrations of serum samples from 44 MPM as compared to 228 controls (68 matched healthy controls, 40 of whom had proven exposure to asbestos, and 160 patients with other inflammatory or malignant lung and pleural diseases). The assay had a sensitivity of 84% for mesothelioma, 37 of 44 patients being detected, and high specificity. Patients with epithelial MPM and larger tumors had higher concentrations of SMRP than those with sarcomatoid histotype and smaller tumor size. In patients for whom serum samples were available at different time points, a trend towards increasing SMRP concentrations with disease progression was observed, while SMRP levels fell after debulking surgery. These early data suggest a possible role of SMRP determination in monitoring response to different therapeutic interventions. Osteopontin is a glycoprotein that is overexpressed in several human tumors such as lung, breast and colon cancer.75,76 Osteopontin mediates cell–matrix interactions; high levels of this molecule correlate with tumor invasion, progression and metastasis. Its expression is regulated by pathways that are associated with asbestos-induced carcinogenesis.77 Pass et al.72 investigated the role of osteopontin in MPM, measuring serum levels of this molecule in 76 patients with MPM and in 114 controls (69 subjects with asbestos exposure and 45 subjects who were not exposed to asbestos). Serum osteopontin levels, detected with an ELISA assay, were significantly higher in patients with MPM, with a sensitivity of 77.6% and a specificity of 85.5%. There were no significant differences in mean serum osteopontin levels among patients with stage I, II or III MPM. Prospective studies with serum osteopontin measurements at different time points are needed to determine the role of this marker in monitoring response to therapy of MPM.
Conclusions Assessment of response with criteria based on CT measurements is challenging in MPM, due to its pattern of growth. Modified RECIST criteria remain the standard methodology of response evaluation, even though modeling of MPM growth challenges the use of PR and PD classifications of the standard RECIST in this disease. Careful consideration must be given to the measurement acquisition process to minimize inter-observer variability. Functional and quality of life parameters remain valuable endpoints in monitoring MPM. In the future, computer-assisted techniques for CT measurement, metabolic imaging with DCE-MRI and FDGPET and use of new serum markers may play a role in assessing response to treatment in this disease.
Conflict of interest statement None declared.
References 1. Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591–603.
Assessment of tumor response in malignant pleural mesothelioma 2. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117:54–65. 3. Robinson BWS, Musk AW, Lake AR. Malignant mesothelioma. Lancet 2005;366:397–408. 4. Ellis P, Davies AM, Evans WK, et al. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. J Thorac Oncol 2006;1:591–601. 5. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–44. 6. Van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organization for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 2005;23:6881–9. 7. Zucali PA, Giaccone G. Biology and management of malignant pleural mesothelioma. Eur J Cancer 2006;42:2706–14. 8. Scagliotti GV, Selvaggi G. Emerging drugs for mesothelioma. Expert Opin Emerging Drugs 2007;12:127–37. 9. Metintas M, Ucgung I, Elbek O, et al. Computer tomography features in malignant pleural mesothelioma and other commonly seen pleural diseases. Eur J Radiol 2002;41:1–9. 10. Marom EM, Erasmus JJ, Pass HI, Patz Jr EF. The role of imaging in malignant pleural mesothelioma. Semin Oncol 2002;29:26–35. 11. Ng CS, Munden RF, Libshitz HI. Malignant pleural mesothelioma: the spectrum of manifestations on CT in 70 cases. Clin Radiol 1999;54:415–21. 12. Heelan RT, Rusch VW, Begg CB, Panicek DM, Caravelli JF, Eisen C. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. Am J Roentgenol 1999;172:1039–46. 13. Hierholzer J, Luo L, Bittner RC, et al. MRI and CT in the differential diagnosis of pleural disease. Chest 2000;118: 604–9. 14. Edwards JG, Stewart DJ, Martin-Ucar A, Muller S, Richard C, Waller DA. The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg 2006;131: 981–7. 15. Carretta A, Landoni C, Melloni G, et al. 18-FDG positron emission tomography in the evaluation of malignant pleural diseases – a pilot study. Eur J Cardiothorac Surg 2000;17: 377–83. 16. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2003;126:11–6. 17. Erasmus JJ, Truong MT, Smythe WR, et al. Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: staging implications. J Thorac Cardiovasc Surg 2005;129: 1364–70. 18. Truong MT, Marom EM, Erasmus JJ. Preoperative evaluation of patients with malignant pleural mesothelioma: role of integrated CT-PET imaging. J Thorac Imaging 2006;21:146–53. 19. Flores RM, Akhurst T, Gonen M, et al. Positron emission tomography predicts survival in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2006;132:763–8. 20. Nowak AK. CT, RECIST, and malignant pleural mesothelioma. Lung Cancer 2005;49(Suppl. 1):S37–40. 21. Nowak AK. Phase II trials in mesothelioma: an increasing challenge. Lung Cancer 2005;50:87–90.
539
22. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14. 23. Solheim OP, Saeter G, Finnanger AM, Stenwig AE. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. Br J Cancer 1992;65:956–60. 24. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. 25. Van Klaveren RJ, Aerts JGJV, De Bruin H, Giaccone G, Manegold JP, Van Meerbeeck JP. Inadequacy of the RECIST criteria for response evaluation in patients with malignant pleural mesothelioma. Lung Cancer 2004;43:63–9. 26. Monetti F, Casanova S, Grasso A, Cafferata MA, Ardizzoni A, Neumaier CE. Inadequacy of the new response evaluation criteria in solid tumors (RECIST) in patients with malignant pleural mesothelioma: report of four cases. Lung Cancer 2004;43:71–4. 27. Byrne MJ, Davidson JA, Musk AW, et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999;17:25–30. 28. Hazarika M, White RM, Booth BP, et al. Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 2005;11: 982–92. 29. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15:257–60. 30. Armato III SG, Oxnard GR, MacMahon H, et al. Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques. Med Phys 2004;31: 1105–15. 31. Armato III SG, Ogarek JL, Starkey A, et al. Variability in mesothelioma tumor response classification. AJR 2006;186: 1000–6. 32. Armato III SG, Oxnard GR, Kocherginsky M, Vogelzang NJ, Kindler HL, MacMahon H. Evaluation of semiautomated measurements of mesothelioma tumor thickness on CT scans. Acad Radiol 2005;12:1301–9. 33. Oxnard GR, Armato III SG, Kindler HL. Modeling of mesothelioma growth demonstrates weakness of current response criteria. Lung Cancer 2006;52:141–8. 34. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998;115:310–7. 35. Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpem EF, Sumher JE. CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques – initial observations. Radiology 2002;225:416–9. 36. Atri M. New technologies and directed agents for applications of cancer imaging. J Clin Oncol 2006;24:3299–308. 37. Fennell D, Steele J, Sheaff M, et al. Response of malignant pleural mesothelioma to chemotherapy does not confer a survival advantage. Lung Cancer 2005;49(Suppl. 2):S220. [abstr. P-397]. 38. Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443–8. 39. Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control Clin Trials 2000;21:343–59. 40. Francart J, Legrand C, Sylvester R, Van Glabbeke M, Van Meerbeeck JP, Robert A. Progression-free survival rate as primary endpoint for phase II cancer clinical trials: application to mesothelioma. The EORTC Lung Cancer Group. J Clin Oncol 2006;24:3007–12. 41. Weber WA. Use of PET for monitoring cancer therapy and for predicting outcome. J Nucl Med 2005;46:983–95.
540 42. Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. New Engl J Med 2006;354: 496–507. 43. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with 18F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002;13:1356–63. 44. Goerres GW, Stupp R, Barghouth G, et al. The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate. Eur J Nucl Med Mol Imaging 2005;32:153–62. 45. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19:3058–65. 46. Weber WA, Petersen V, Schmidt B, et al. Positron emission tomography in non-small cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol 2003;21:2651–7. 47. Ceresoli GL, Chiti A, Zucali PA, et al. Early evaluation in malignant pleural mesothelioma by positron emission tomography with [18F] fluorodeoxyglucose. J Clin Oncol 2006;24: 4587–93. 48. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer 1999;35:1773–82. 49. Weber WA, Wieder H. Monitoring chemotherapy and radiotherapy of solid tumors. Eur J Nucl Med Mol Imaging 2006;33(Suppl. 13):S27–37. 50. Flores RM, Akhurst T, Krug L, et al. Decreased PET SUV after induction chemotherapy is associated with improved survival in malignant pleural mesothelioma (MPM). Proc Am Soc Clin Oncol 2005;23:636S. [abstr 3690]. 51. Steinert HC, Santos Dellea MM, Burger C, et al. Therapy response evaluation in malignant pleural mesothelioma with integrated PET-CT imaging. Lung Cancer 2005;49(Suppl. 1): S33–5. 52. Byrne M, Francis R, Van der Schaaf A, et al. Comparison of FDG-PET and CT scans to assess response to chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer 2005;49(Suppl. 2):S220. [abstr. O-074]. 53. Kimura T, Yoshimura N, Mitsuoka S, et al. Monitoring of chemotherapy response in multiple disseminated malignant pleural mesothelioma using fluorodeoxyglucose positron emission tomography. Proc Am Soc Clin Oncol 2005;23:664S. [abstr. 7177]. 54. Power D, Murphy C, Farrelly C, et al. Prediction of response to chemotherapy in malignant pleural mesothelioma: early positron emission tomography versus computed tomography. Lung Cancer 2005;49(Suppl. 2):S227. [abstr. P-424]. 55. Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol 2006;24:3282–92. 56. Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol 2006;24: 3293–8. 57. Giesel FL, Bischoff H, Von Tengg-Kobligk H, et al. Dynamic contrast-enhanced MRI of malignant pleural mesothelioma. A feasibility study of noninvasive assessment, therapeutic followup, and possible predictor of improved outcome. Chest 2006;129:1570–6. 58. Steele JPC, Shamash J, Evans MT, et al. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 2000;18:3912–7. 59. Andreopoulou E, Ross PJ, O’Brien MER, et al. The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma. Ann Oncol 2004;15:1406–12.
G.L. Ceresoli et al. 60. Muers MF, Rudd RM, O’Brien MER, et al. BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112. Thorax 2004;59:144–8. 61. Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Adapting the Lung Cancer Symptom Scale (LCSS) to mesothelioma. Using the LCSS-Meso conceptual model for validation. Cancer 2004;101:587–95. 62. Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Measuring quality of life in patients with pleural mesothelioma using a modified version of the Lung Cancer Symptom Scale (LCSS): psychometric properties of the LCSS-Meso. Support Care Cancer 2006;14:11–21. 63. Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: results of the randomized pemetrexed+cisplatin vs. cisplatin trial using the LCSS-Meso instrument. Proc Am Soc Clin Oncol 2003;22. [abstr 7177]. 64. Nowak AK, Stockler MR, Byrne MJ. Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire and Lung Cancer module. J Clin Oncol 2004;22:3172–80. 65. Paoletti P, Pistolesi M, Rusthoven JJ, et al. Correlation of pulmonary function tests with best tumor response status: results from the phase III study of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma. Proc Am Soc Clin Oncol 2003;22. [abstr. 2651]. 66. Plathow C, Klopp M, Schoebinger M, et al. Monitoring of lung motion in patients with malignant pleural mesothelioma using two-dimensional and three-dimensional dynamic magnetic resonance imaging. Comparison with spirometry. Invest Radiol 2006;41:443–8. 67. Curran D, Sahmoud T, Therasse P, Van Meerbeeck J, Postmus G, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998;16: 145–52. 68. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998;113:723– 31. 69. Frebourg T, Lerebours G, Delpech B, et al. Serum hyaluronate in malignant pleural mesothelioma. Cancer 1987;59: 2104–7. 70. Schouwink H, Korse CM, Bonfrer JMG, Haart AA, Baas P. Prognostic value of the serum markers Cyfra 21-1 and tissue polypeptide antigen in malignant mesothelioma. Lung Cancer 1999;25:25–32. 71. Robinson BWS, Creaney J, Lake R, et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612–6. 72. Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. New Engl J Med 2005;353:1564–73. 73. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancer. PNAS 1996;93:136–40. 74. Scholler N, Fu N, Yang Y, et al. Soluble members of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. PNAS 1999;96:11531–6. 75. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7: 4060–6.
Assessment of tumor response in malignant pleural mesothelioma 76. Martinetti A, Bajetta E, Ferrari L, et al. Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrazole. Endocr Relat Cancer 2004;11:771–9.
541
77. Sandhu H, Dehnen W, Roller M, Abel J, Unfried K. mRNA expression patterns in different stages of asbestos-induced carcinogenesis in rats. Carcinogenesis 2000;21:1023–9.